¹Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York, USA

Correspondence: Dr C Michael DiPersio, Center for Cell Biology and Cancer Research, Albany Medical College, Mail Code 165, Room MS-326, 47 New Scotland Avenue, Albany, New York 12208-3479, USA. E-mail: dipersm@mail.amc.edu

²These authors contributed equally to this work.

Received 11 January 2007; Revised 12 June 2007; Accepted 3 July 2007; Published online 30 August 2007.

Abstract

Transforming growth factor- (TGF) signaling pathways regulate a number of keratinocyte functions during epidermal carcinogenesis and wound healing, including proliferation, survival, and migration. TGF can induce expression of the matrix metalloproteinase-9 (MMP-9), which has critical roles in promoting extracellular matrix remodeling and angiogenesis during tumorigenesis and tissue repair. Integrin 31 is a cell adhesion receptor for laminin-332/laminin-5 with important roles in the survival and motility of epidermal keratinocytes. We previously reported that 31 induces the expression of MMP-9 in immortalized keratinocytes. In this study, we show that endogenous TGF is required for maximal MMP-9 expression, and that 31 is required for full induction of MMP-9 protein and mRNA in response to TGF. This regulation was not observed in non-immortalized, primary keratinocytes, indicating that coordinate regulation of MMP-9 by 31 and TGF is a property of immortalized cells. 31 did not regulate endogenous TGF gene expression, TGF bioavailability, or TGF-Smad signaling. However, the combined inductive effects of TGF and 31 on MMP-9 were suppressed by a Src family kinase (SFK) inhibitor, indicating involvement of a SFK pathway. These findings provide early evidence of a role for 31 in augmenting TGF-mediated induction of MMP-9 in immortalized or transformed keratinocytes during skin carcinogenesis.